Susceptibility to AS is highly heritable, with heritability assessed in twins at >97%. Whilst the major gene for the disease is HI_A-B27, there is strong epidemiologic and genetic evidence that other genes also contribute significantly. In the previous cycle of funding, TASC played a major role in identifying all 23 genes other than HI-A-B27 which have had confirmed association with AS. These findings have had major impacts on research into the causation of AS, including the mechanism by which HLA-B27 causes AS, and have led to early translational studies in treatment and genetic diagnostics. It is clear that many more genes remain to be identified in AS, and that at most loci, we have not yet clearly identified the key associated variant(s). We will address both these issues over the next five years. Project 1 will have two aims: Aim 1: To identify novel genetic associations with AS not previously identified by tagSNP studies, exome chip genotyping, using a novel exome-chip which will genotype 220,000 exonic variants representing all exonic variants reported in white Europeans to date with >0.1% minor allele frequency, will be carried out in 8,000 AS cases of white European ancestry that we have available to us already, and 10,000 healthy common controls. This study is likely to help refine the true disease-associated regions better, by adding to the information about rare, likely functional, variants in known AS-associated regions. Aim 2: To identify the both common and rare disease-causative variants underlying loci associated with AS, all known regions associated with AS will be targetted, and the genetic variation in these regions comprehensively characterized by a combination of case resequencing and bioinformatic mining of public datasets such as the 1000 Genomes data. Hybridization capture will be utilized to perform focused resequencing of disease-associated regions. Sequencing will be carried out in 1,000 AS cases in order to ensure detection of even rare variants. A follow-up genotyping study will then be performed to test the association of these variants in a large cohort (at least 8,000 cases and ethnically matched controls).